Itziar de Aguirre Egaña

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1 Universitat Autònoma de Barcelona Facultat de Medicina PhD programme: Departamento de Medicina Interna Thesis entitled: LKB1/ AMPK / TSC2 signaling pathway alterations in Non-Small-Cell-Lung-Carcinoma Present by: Itziar de Aguirre Egaña Thesis Advisors: Director: Dr. Paula Vertino Director: Dr. Rafael Rosell i Costa Itziar de Aguirre Egaña Dr. PM Vertino Dr. Rafael Rosell Costa Badalona, 2014

2 Paula M. Vertino, Professor at the Department of Radiation Oncology at Emory University School of Medicine and leader of Cancer Genetics and Epigenetics Program, Winship Cancer Institute of Emory University (Atlanta, Georgia). CERTIFICA Que la Tesi Doctoral titulada: LKB1/ AMPK / TSC2 signaling pathway alterations in Non-Small-Cell- Lung-Carcinoma, ha estat realitzada per la llicenciada Itziar de Aguirre Egaña sota la seva direcció, en codirecció amb el Dr. Rafael Rosell i Costa, i considera que és apta per a la seva defensa pública davant d un Tribunal per optar al grau de Doctora per la Universitat Autònoma de Barcelona. I per tal que quedi constància, signa aquest document. Dra. Paula M. Vertino Badalona, Juny 2014

3 En Rafael Rosell i Costa, Professor Associat del Departament de Medicina de la Universitat Autònoma de Barcelona i director del Cancer Biology & Precision Medicine Program de l Institut Català d Oncologia, Hospital Universitari Germans Trias i Pujol, CERTIFICA Que la Tesi Doctoral titulada: LKB1/ AMPK / TSC2 signaling pathway alterations in Non-Small-Cell- Lung-Carcinoma, ha estat realitzada per la llicenciada Itziar de Aguirre Egaña sota la seva direcció, en codirecció amb la Dra. Paula M.Vertino, i considera que és apta per a la seva defensa pública davant d un Tribunal per optar al grau de Doctora per la Universitat Autònoma de Barcelona. I per tal que quedi constància, signa aquest document. Dr. Rafael Rosell i Costa Badalona, Juny 2014

4 Acknowledgements These lines are to deserve my sincere acknowledgment to all the people who helped me to develop this work: First of all, words cannot express how grateful I feel toward my advisors, Paula M. Vertino and Rafael Rosell i Costa, each of them is a great scientist and an expert in their field. Thanks to Paula M. Vertino for her kindness providing unlimited support over the last years, without her guidance and supervision have not been able to develop this research. Also I m grateful to her to motivate me in difficult moments and for all she kindly taught me about molecular biology. A massive thank you to Rafael Rosell i Costa, for the opportunity he offered me to live my american experience. It was a very rich, an extremely useful, and a fruitful experience. Thanks to Wei Zhou, Diansheng Zhong and Michael, lovely people who always had the willingness to help with a big smile. Thanks for their generosity. I would like to thank Vertino s lab : Krithika Subramanian, Doris Powell, Melissa Pourpak, Annalisa Stoney and Mary Lucas Smith, for their help in the laboratory and the excellent time I enjoyed working and entertaining with them. You made me feel at home!!! Many thanks to Professor Xavier León Vintró, a generous person who without knowing me, he developed the statistical analysis of this thesis, at a time when it was not any exit. I m grateful to Pedro Lopez de Castro, for his contribution in the tedious and laborious step of collecting the clinical data of patients analyzed. I m grateful to Jose Luis Mate, for his cooperation from the Department of Pathology. I would also like to thank all members of the Oncology Service, Hospital Germans Trias i Pujol, they always found time to answer my queries. Last but certainly not least, I would like to express my enormous gratitude to all my family and friends for their unlimited support, unconditional encouragement and patience. It would take too long to acknowledge everyone by name, but you know who you are, to all of you ESKERRIK ASKO, MOLTES GRÀCIES, THANKS!!!

5 INDEX INDEX Page Abbreviations...IV I. Introduction Lung Cancer Epidemiology of Lung Cancer Incidence Mortality Lung cancer causes Types of Lung Cancer SCLC NSCLC Stage of lung cancer Stages of Small Cell Lung Cancer Stages of Non-Small Cell Lung Cancer Epigenetic alterations in DNA Epigenetic modifications X chromosome inactivation Genomic imprinting DNA methylation What is methylation? Distribution of methylated cytosines and CpG islands DNA methyltransferases DNA Methyation in Cancer Techniques to study DNA methylation Clinical implications of DNA methylation Methylation &Tumor suppressor genes Chromatin and Methylation Histone Acetylation/ Deacetylation Histone deacetylase and Methyl-binding domain

6 INDEX 3. Tumor suppressor genes & familial cancer Peutz Jeghers Syndrome (PJS) PJS & LKB LKB Posttranslational modifications of LKB LKB1 functions Regulation of LKB1: LKB1-STRAD-MO25 complex LKB1 & Lung Cancer LKB1/ AMPK/ TSC pathway AMP-activated protein kinase (AMPK) LKB1 activates 12 kinases of AMPK family Tuberous sclerosis complex (TSC) Rheb (Ras-homolog enriched in brain ) /mtor (target of rapamacyn), downstream effectors of LKB1/AMPK/TSC pathway II. Rationale III. Objectives IV. Material & Methods Cell Lines NSCLC Paraffin Embedded Tissues Acid Nucleic isolation from cell line Genomic DNA isolation RNA isolation Genomic DNA isolation from Paraffin Embedded Tissue DNA isolation Mutations of LKB1/AMPK/TSC Analysis of LKB1 and AMPK mutations by DNA sequencing Protein truncation analysis of TSC Bisulfite modification-msp Reverse transcription-polymerase chain reaction (RT-PCR) Quantitative PCR real-time (qrt-pcr) Reagents and 5-aza-dC and TSA treatment

7 INDEX 15. LKB1 small interfering RNA treatment Cell Lysis & Protein extraction Assessment of protein Western Blotting V. Results Genetic and Epigenetic alterations in LKB1/AMPK/TSC LKB1 activates 12 kinases of AMPK subfamily Determine the BRSK2 expression in a panel of 23 cell lines BRSK2 methylation status in paraffin embedded tumor tissues Inhibition of LKB1 Protein expression via sirna VI.Discussion Aim I. Determine the frequency of LKB1/AMPK/TSC2 signaling pathway alterations in NSCLC Aim II. Study LKB1/AMPK-related kinases alterations as an additional molecular mechanism for the development of lung cancer Aim III. Consequences of BRSK2 methylation Aim IV. Clinical validation of BRSK2 methylation status, in paraffin embedded tumor tissues of patients with lung cancer Aim V. Inhibition of LKB1 protein on NSCLC cell lines VII.Conclusions VIII. References

8 ABBREVIATIONS Abbreviations 1x TE 1 mm Tris-HCl (ph 7.5), 1 mm EDTA, sterile solution. 4EBP1 Eukaryote initiation factor 4E Binding Protein 1 5aza-Dc 5-azadeoxycytidine AC Adenocarcinoma ADP Adenosine diphosphate AJCC American Joint Committee on Cancer AKT Serine/threonine protein kinase B AMPK AMP-activated protein kinase APC Adenomatous Polyposis Coli ASC Adenosquamous ATCC American Type Culture Collection ATM Ataxia-Telangiectasia-Mutated kinase ATP Adenosine-5'-triphosphate BAC Bronchioloalveolar carcinoma bp Base pairs BRSK Brain Specific protein Kinase C Cytosine CBS domain Cystathionine β-synthase domain CH 3 Methyl group CO 2 Carbon dioxide COPD Chronic Obstructive Pulmonary Disease Cys Cysteine DECP Diethylpyrocarbonate DNA Deoxyribonucleic acid DNMT DNA-5-methyltransferase EDTA Ethylenediaminetetraacetic acid FBS Fetal bovine serum GADPH glycerradehyde 3-phophate dehydrogenase GAP GTPase- activating protein GBD Glycogen-Binding Domain

9 ABBREVIATIONS GTP Guanosine triphosphate GTPase Family of hydrolase enzymes that can bind and hydrolyze GTP HDAC Histone Deacetylase IGF1 Insulin-like growth factor1 IRS1 Insulin Receptor Substrate-1 LCC Large cell carcinoma LKB1 l LKB1 splice variant, generate a protein of 50-kDa LKB1 Serine-Threonine Protein Kinase, LKB1 s LKB1 splice variant, generate a protein of 48-kDa LOH Loss of Heterozygosity MAPK Mitogen Activated Protein Kinase MARK MAP/ microtubule affinity regulating kinase MBD Methyl Binding Domain MDR1 Multidrug resistance gene 1 MECP2 5-Methyl-cytosine binding protein MgCl2 Magnesium chloride MGMT O6-methylguanine-DNA-methyltransferase M-MLV retrotranscriptase Moloney Murine Leukemia Virus retrotranscriptase MO25 Mouse protein 25 mrna Messenger Ribonucleic Acid MSP Methylation Specific PCR mtor Mammalian Target of Rapamycin NaOH Sodium hydroxide NH4SO4 Ammmonical Nitrogen NSCLC Non Small Cell Lung Cancer PAR Partitioning defective gene family PCR Polymerase Chain Reaction PI3K phosphoinositide 3-kinase PIP3 Phosphatidylinositol 3,4,5-triphosphatase PJS Peutz-Jeghers Syndrome PKA camp-dependent protein kinase

10 ABBREVIATIONS PTEN Phosphatase and tensin homolog PTT Protein Truncation Test PVDF Polyvinylidene fluoride membrane qrt-pcr Quantitative PCR real-time RARβ Retinoic Acid Receptor β RB Retinoblastoma tumor-suppressor Rheb Ras-homolog enriched in brain RNA Ribonucleic acid RNase Ribonuclease RPMI Roswell Park Memorial Institute medium RSK p90 ribosomal S6 protein kinase RT-PCR Reverse Transcription Polymerase Chain Reaction S6K p70 ribosomal S6 kinase 1 SAD Synapses of amphids defective SAM S-adenosylmethionine SCC Squamous cell carcinoma SCLC Small Cell Lung Cancer SDS Sodium dodecyl sulfate SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis sirna Small interfering RNA STK11 Serine-Threonine Protein Kinase, STRAD STe20 Relater ADaptor, T Thymine TNM Tumor Node Metastasis TSA Trichostatin A TSC Tuberous Sclerosis Complex TSG Tumor Supressor Gene UBA Ubiquitin Associated UICC Union for Cancer Control WHO World Health Organization WPWS Wolff-Parkinsin-White syndrome

11 I. Introduction

12 INTRODUCTION 1. Lung Cancer 1.1 Epidemiology of Lung Cancer Incidence Cancer is one of the leading causes of morbidity and mortality worldwide (Peto 2001). According to GLOBOCAN 2012 (Ferlay J 2013), an estimated 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred in 2012, compared with 12.7 million and 7.6 million, respectively, in Prevalence estimates for 2012 show that there were 32.6 million people (over the age of 15 years) alive who had had a cancer diagnosed in the previous five years. The most commonly diagnosed cancers worldwide were those of the lung (1.8 million, 13.0% of the total), breast (1.7 million, 11.9%), and colorectum (1.4 million, 9.7%) Figure 1. Figure 1. The most commonly diagnosted cancers worldwide. Excluding non melanoma skin cancer, 2012 estimates. The data are derived from the IARC GLOBOCAN 2012 database (Ferlay J 2013). Projections based on the GLOBOCAN 2012 (Ferlay J 2013) estimates predict a substantive increase to 19.3 million new cancer cases per year by 2025, due to growth and ageing of the global population. More than half of all cancers (56.8%) and cancer deaths (64.9%) in 2012 occurred in less developed regions of the world, and these proportions will increase further by

13 INTRODUCTION Lung cancer has been estimated as the most common cancer in the world for se veral decades (Figure 2) (Ferlay J 2010), (Parkin, Stjernsward et al. 1984), (Parkin, Laara et al. 1988; Parkin, Pisani et a l ), (Parkin, P isani et a l ), (Parkin, Bray et al ). An estimated 1.61 million people across the world were diagnosed with lung cancer in 2008, accounting for 13% of the total. Figure 2. T rends in the R anking o f New Ca ses of Ca ncer Wo rldwide, The d ata are derived from the IARC GLOBOCAN 2008 database.globocan 2008 (Ferlay J 2010). Lung cancer has a high incidence in both developing countries and areas undergoing economic development such a s China (Parkin 2002 ). Although thes e r egional differences mi ght be explained b y genetic di fferences a mong popula tions, variations in lifestyles, environmental exposures and medical practices such as screening are also likely to be important determinants of cancer risk. This assumption is reinforced b y migration pa tterns that show that incide nce of cancer among mi grants more c losely r eflects the ra tes in the adoptive c ountry. Lung can cer incidence rates are highest in Europe and Northern America and lowest in parts of Africa (Figure 3). More than half (55%) of the cases occurred in the developing world (Ferlay J 2010)

14 INTRODUCTION Figure 3. Incidence of lung cancer. There is substantial global variability in lung cancer incidence (measures as age-standardized rates) occurring in people living in development countries. Lung cancer incidence is currently high in development countries as well as those countries undergoing economic transition us China. (Ferlay J 2013). The disease remains as the most common cancer in men worldwide (1.2 million, 16.7% of the total) with the highest estimated age-standardised incidence rates in Central and Eastern Europe (53.5 per 100,000) and Eastern Asia (50.4 per 100,000). Notably low incidence rates are observed in Middle and Western Africa (2.0 and 1.7 per 100,000 respectively) (Figure 4). In women, the incidence rates are generally lower and the geographical pattern is a little different, mainly reflecting different historical exposure to tobacco smoking. Thus the highest estimated rates are in Northern America (33.8) and Northern Europe (23.7) with a relatively high rate in Eastern Asia (19.2) and the lowest rates again in Western and Middle Africa (1.1 and 0.8 respectively) (Figure 5)

15 INTRODUCTION Figure 4. Incidence / mortality of Lung Cancer in Males by World Regions. (Ferlay J 2013). Figure 5. Incidence / Mortality of Lung Cancer in Females by World Region. (Ferlay J 2013)

16 INTRODUCTION Mortality Deaths from c ancer in the world are pr ojected to continue rising, influe nced in part by an increasing and aging global population. Lung cancer is the most common c ause of de ath from cancer worldwide, e stimated to be responsible for nearly one in five (1.59 million deaths, 19.4% of the total) (Figure 6). Because of its high f atality (the ov erall r atio of mort ality t o incide nce is 0.87) a nd the relative lack of variability in survival in different world regions, the geographical patterns in mortality closely follow those in incidence. Figure 6. The most co mmonly ca uses o f ca ncer death worldwide. Excluding n on m elanoma skin. ca ncer, esti mates. The data are derived f rom th e IARC G LOBOCAN database (Ferlay J 2013). Due to the long time-lag between exposure to lung cancer risk factors, such as smoking, and the onset of the disea se it self, lung cancer incidence a nd morta lity for wo men and m en tends to reflect prior and long-term exposures to risk. Broadly speaking, patterns of lung cancer incidence and mortality show higher rates of the disease among men than women (Figure 4-Figure 5). In the United States of A merica (U SA), fo r example, in 2000 the age-adjusted lung c ancer incidence rate was 79.7 per population for males, compared with a rate of 49.7 per for fe males (SEER 2003 ). Similarly, in the United King dom, the age-standardized lung cancer incidence ra te among male s is approximately twice that in women (70.4 pe r population in men and 34.9 per popul ation in females in 1999) (Cancer.Research.UK - 6 -

17 INTRODUCTION 2003). But in 2012, lung cancer was expected to account for 26% of all female cancer deaths and 29% of all male cancer deaths (American Cancer Society 2012). Lung cancer accounts for more deaths than any other cancer in both men and women. An estimated 160,340 deaths, accounting for about 28% of all cancer deaths, are expected to occur in 2012 (American Cancer Society 2012). Death rates began declining in men in 1991; from 2004 to 2008, rates decreased 2.6% per year. Lung cancer death rates did not begin declining in women until 2003; from 2004 to 2008, rates decreased by 0.9% per year. Gender differences in lung cancer mortality patterns reflect historical differences between men and women in the uptake and reduction of cigarette smoking over the past 50 years (American Cancer Society 2012). 1.2 Lung cancer causes Smoking Lung cancer is unique among human solid cancers in that a single environmental factor-tobacco smoke- is believed to promote sequential changes in target cells that lead to carcinogenesis. The first references on the carcinogenic effect of the tobacco are of more than 200 years ago in the book Cautions against the inmoderate uses of snuff and the book: Chirurgical Observations published on 1775 by the Dr. Percivall Pott. It was not until 1914 that the carcinogenic nature of the contained hydrocarbons was demonstrated in the solid and tarred particles of the tobacco smoke (Yamagawa and Ichikawa 1915). Manufactured cigarettes were introduced at the beginning of the twentieth century. Since then the global consumption of cigarettes has been rising progressively. While consumption is leveling off, and even decreasing in some countries, worldwide more people are smoking and they are smoking more cigarettes. The numbers of smokers will increase mainly due to expansion of the world s population. Pipe and cigar smoking can also cause lung cancer, although the risk is not as high as with cigarette smoking (Wald and Watt 1997).While someone who smokes one pack of cigarettes per - 7 -

18 INTRODUCTION day has a risk for the development of lung cancer that is 25 times higher than a nonsmoker, pipe and cigar smokers have a risk of lung cancer that is about five times that of a nonsmoker. In former smokers, the risk of developing lung cancer begins to approach that of a nonsmoker about 15 years after cessation of smoking. In Europe the percentage of smokers is about 30%. Overall, ~33% of the adult world population smokes; this equates to 1.1 billion people (of which 200 million are women). The percent of the male population that smokes is 47% while the rate among females is 12%. In developing countries, the percentages are 48% in men and 7% in women, while in the developed countries 42% of the men are smoking and 24% of women (Fuster, O'Rourke et al. 2005). At the moment it is believed that 90% of all the deaths for lung cancer are caused by tobacco. Worldwide, tobacco use causes more than 5 million deaths per year. In total, tobacco use is responsible for the death of about 1 in 10 adults worldwide (WHO 2011). Based on the current trends, the World Health Organization (WHO) predicts that by the year 2020, tobacco will cause in the world more than 10 million deaths a year, (Warren, Jones et al. 2008), causing more deaths than AIDS, tuberculosis, traffic accidents, deaths at birth, suicide and homicides together. Passive smoking The National Cancer Institute s 10th Smoking and Tobacco Control Monograph reviewed studies published between 1991 and 1997 in the United States, Europe, and Asia (Wu 1999). It included studies on environmental tobacco smoke exposure from spouses and the workplace and exposure in other social settings. They concluded that environmental tobacco smoke exposure resulted in an excess risk of 20% for developing lung cancer in the never smokers. Asbestos fibers Asbestos fibers are silicate fibers that can persist for a lifetime in lung tissue following exposure to asbestos. The workplace is a common source of exposure to asbestos fibers, as asbestos was widely used in the past for both thermal and acoustic insulation materials. Lung cancer can occur in nonsmokers exposed to asbestos; however, the risk is magnified several-fold by smoking (Boffetta 2004)

19 INTRODUCTION Cigarette smoking drastically increases the chance of developing an asbestos-related lung cancer in exposed workers. Workers exposed to asbestos who do not smoke have a fivefold greater risk of developing lung cancer than nonsmokers not exposed to asbestos, and those asbestos workers who smoke have a risk that is 50 to 90 times greater than nonsmokers. Environmental and occupational exposures People in developing countries are exposed to broader ranges of occupational and environmental risks, as more people are involved in manufacturing, farming, mining or other industrial occupations than developed countries. Research in China, for instance, has shown a positive association between lung cancer and radon gas exposure (Lubin, Wang et al. 2004), which is high in some homes and among underground miners. Radon gas is a natural, chemically inert gas that is a natural decay product of uranium. An estimated 12% of lung cancer deaths are attributable to radon gas. As with asbestos exposure, concomitant smoking greatly increases the risk of lung cancer with radon exposure. In both China and India, indoor air pollution due to burning of coal and biomass for cooking and heating in homes has also been associated with lung cancer (Kleinerman, Wang et al. 2000; Smith 2000). Air Pollution Air pollution from vehicles, industry, and power plants can raise the likelihood of developing lung cancer in exposed individuals. Up to 1% of lung cancer deaths are attributable to breathing polluted air, and experts believe that prolonged exposure to highly polluted air can carry a risk similar to that of passive smoking for the development of lung cancer. Genetic predisposition While the majority of lung cancers are associated with tobacco smoking, the fact that not all smokers eventually develop lung cancer suggests that other factors, such as individual genetic susceptibility, may play a role in the causation of lung cancer. Genetic variation causes many metabolic differences between individuals, and there is much interest in understanding the potential impact of this variation on susceptibility to cancer and - 9 -

20 INTRODUCTION cancer pathogenesis. Specific mutations in single genes have been reported to greatly increase the risk of some types of cancer, although the prevalence of these mutations is rare at a population level. By contrast, common genetic polymorphisms that contribute only a modest variation in risk can have a greater impact on public health, especially in conjunction with environmental exposures. Lung diseases The presence of certain diseases of the lung, notably chronic obstructive pulmonary disease (COPD), is associated with a slightly increased risk (four to six times the risk of a nonsmoker). Survivors of lung cancer have a greater risk than the general population of developing a second lung cancer. Survivors of non-small cell lung cancers, have an additive risk of 1% -2% per year for developing a second lung cancer. In survivors of small cell lung cancers (SCLCs), the risk for development of second cancers approaches 6% per year. Diet So far, much of the diet and cancer research conducted in developing nations has focused on specific diet components. There are many dietary variations, especially among populations in Asia, Africa or Latin America, that might be associated with disease risk (Rastogi, Hildesheim et al. 2004). Turmeric, a yellow-colour spice and flavor commonly consumed by millions of people, particularly in South Asia, has traditionally been used as a remedy for liver ailment. Curcumin, a constituent of turmeric, is a phytochemical that is currently being researched for its anti-tumour properties, such as inducing cell-growth inhibition and apoptosis. Age The population of the world is ageing; this is important because cancer predominantly affects older people. Almost 70% of people diagnosed with the condition are over 65 years of age, while less than 3% of cases occur in people under age

21 INTRODUCTION The median age increased from 23.5 years in 1950 to 26.4 years in By 2050, the median age is projected to reach 37.8 years. The proportion of people in the world aged 60 or older will rise from the current 10% to 22% in 2050 (UnitedNations 1999). There are big variations in the age structures of populations of more developed compared with less developed countries (UnitedNations 1999) (Ferlay J.B.F 2004). Currently 20% of the populations in the more developed regions are aged over 60 compared with 8% in the less developed regions. By 2050 these proportions are expected to rise to 33% and 19% respectively. The countries with the oldest populations in the world include Italy, Japan and Germany and the countries with the youngest include Uganda, Niger and Yemen (UnitedNations 1999). World life expectancy at birth is now at 65 years, having increased by a remarkable 20 years since By 2050, life expectancy is expected to exceed 76 years (UnitedNations 1999). 1.3 Types of Lung Cancer Lung cancers are broken down into two major types, small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC). This classification is based upon the microscopic appearance of the tumor cells themselves. These two types of cancers grow and spread in different ways, so a distinction between these two types is important SCLC Small cell lung cancers comprise approximately 20-25% of all lung cancer cases. SCLC is strongly related to cigarette smoking, with only 1% of these tumors occurring in nonsmokers. This type of lung cancer originates in an inner layer of the walls of the bronchi called the bronchial submucosa, and grows aggressively (in comparison with non small cell lung cancers), quickly spreading into surrounding tissues, and ultimately, through the body. Symptoms are generally not noticeable until the cancer has spread into other parts of the body. Because of their rapid growth pace and tendency to metastasize, small cell cancers are described with only two stages, limited when spread is contained to the localized area of the lung and immediate surrounding tissues, and extensive when the cancer has spread throughout the body

22 INTRODUCTION Referring to a specific cell type often seen in SCLC, these cancers are sometimes called oat cell carcinomas NSCLC NSCLC are the most common lung cancers, accounting for about 80% of all lung cancers. NSCLC can be divided into three main types that are named based upon the type of cells found in the tumor: Adenocarcinomas are the most commonly seen type of NSCLC. While adenocarcinomas are associated with smoking like other lung cancers, this type is especially observed as well in nonsmokers who develop lung cancer. Most adenocarcinomas arise in the outer, or peripheral, areas of the lungs. The most frequents subtypes are: acinar adenocarcinoma, papillary adenocarcinoma, micropapillary and solid (Travis, Brambilla et al. 2011). Squamous cell carcinomas were formerly more common than adenocarcinomas; at present, they account for about 30% of NSCLC. Cancer that begins in squamous cells, which are thin, flat cells that look like fish scales. Also known as epidermoid carcinomas, squamous cell cancers arise most frequently in the central chest area in the bronchi. Large cell lung cancer sometimes referred to as undifferentiated carcinomas, are the least common type of NSCLC. 1.4 Stage of lung cancer Stages of Small Cell Lung Cancer The objectives of staging in SCLC are to identify localized disease, for which radiation therapy may be suitable, and to quantify the extent of the disease before therapy. Small cell lung cancer is typically classified according to the 2-stage system development by the Veterans Administration Lung Cancer Study Group: Limited stage: when spread is contained to the localized area of the lung and immediate surrounding tissues. Extensive stage: cancer is found in tissues of the chest outside of the lung in which it began or cancer is found in distant organs, therefore when the cancer has spread throughout the body

23 INTRODUCTION Stages of Non-Small Cell Lung Cancer The International Staging System for Lung Cancer has provided a common language for communication about patients with this disease, and the scientific community has been served well by its application. This system classifies the extent of disease based mostly on anatomic information on the extent of the primary tumor, regional lymph nodes, and distant metastases. This classification was developed in the 1940s by Pierre Denoix PF of France and formalized by the Union for Cancer Control (UICC) in the 1950s with the formation of the Committee on Clinical Stage Classification and Applied Statistics. The American Joint Committee on Cancer (AJCC) was founded in 1959 to complete this work. The classification of malignant tumors is according to tumor-node-metastasis (TNM) that describes the extent of a person s cancer. But the concept of stage grouping came later ((UICC) 1988). The TNM system is based on 3 key pieces of information T describes the size of the original (primary) tumor and whether it has grown into nearby areas. N describes the spread of cancer to nearby (regional) lymph nodes that are involved. M describes distant metastasis (spread of cancer from one part of the body to another). Revisions in stage grouping of the TNM subsets in the schema of the International System for Staging Lung Cancer were made to provide greater specificity for identified patient with similar prognoses and treatment options (Table1-Table2). The rules of classification and staging correspond to those appearing in the seventh edition of the AJCC Cancer Staging Manual 2009 and have approval of all national TNM committees

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